This competitive renewal grant proposes to pursue an integrated approach to investigate both peripheral thyroid hormone metabolism and the central regulation of pituitary TSH release in man. Major studies proposed include: autoregulatory conversion of thyroxine (T4) to triiodothyronine (T3) in states of T4 deficiency and excess, alterations in T4 to T3 conversion that occur with fasting and nonthyroidal illnesses (NTIs) and the role of T4 and other hormonal factors in regulating pituitary TSH release in man. These studies of peripheral thyroid hormone metabolism will focus on the importance of propylthiouracil (PTU) non-sensitive, 5'deiodinase (5'D) enzyme systems in regulating T4 to T3 conversion as well as delineating alternate pathways of T4 disposal including T4SO4, T3SO4 and a 'hidden pool" of rT3 generation. Testable models are proposed relating to the source and mechanisms controlling circulating T3 and rT3 levels generated from T4. Paradoxical alterations of thyroid hormone metabolism in patients infected with the human immunodeficiency virus (HIV) will also be investigated. This unusual model may provide important insights into the mechanisms and the metabolic consequences of the changes normally seen in thyroid hormone metabolism with NTIs. The central TSH regulation studies will include a systematic evaluation of the acute and chronic inhibitory effects of T4, T3, triiodothyroacetic acid (T3AC) and other thyroid hormone analogs on serum TSH levels using a uniquely sensitive TSH assay. Actions of TRH, glucocorticoids, dopamine and somatostatin on TSH release will also be assessed. Thyroid function, measured as thyroidal iodine release (TIR) and/or serum thyroglobulin (Tg), will be performed in certain instances as indicators of TSH action on the thyroid gland. These studies will develop data concerning the normal dose-response relationship between circulating thyroid hormones and TSH as well as provide information regarding the mechanism by which the thyroid hormone-pituitary TSH setpoint may be altered in a variety of pathophysiologic states. This multifaceted program will provide a comprehensive view of the central and peripheral systems controlling normal thyroid physiology and alterations occurring in a variety of disease states affecting man.